Distribution Plasticity of the Human Estrogen Receptor α in Live Cells: Distinct Imaging of Consecutively Expressed Receptors

Pick, Horst; Jankevics, Hanna; Vogel, Horst

doi:10.1016/j.jmb.2007.10.007

Cited by 11 publications

(12 citation statements)

References 56 publications

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“…For achieving efficient throughput for detecting estrogenic activities we used fluorescence microscopy to first analyze changes in the intranuclear distribution of a functional ER-YFP chimera, obtained by fusing ER to the yellow fluorescent protein YFP, and then to investigate receptor mobility. Previous studies have shown that ER-activating compounds alter the nucleoplasmic distribution of fluorescent ER chimera from a diffuse to a punctuate pattern (14,(45)(46)(47)(48), which correlates with mobility changes of ER (measured by fluorescence recovery after photobleaching and FCS) due to interactions with nuclear DNA and multiple proteins (21, 49 -53). We discovered two structurally different types of odorants, which induce within minutes after application nuclear aggregation of ER (Fig.…”

Section: Resultsmentioning

confidence: 91%

Dual Activities of Odorants on Olfactory and Nuclear Hormone Receptors

Pick

Etter

Baud

et al. 2009

Journal of Biological Chemistry

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We have screened an odorant compound library and discovered molecules acting as chemical signals that specifically activate both G-protein-coupled olfactory receptors (ORs) on the cell surface of olfactory sensory neurons and the human nuclear estrogen receptor ␣ (ER) involved in transcriptional regulation of cellular differentiation and proliferation in a wide variety of tissues. Hence, these apparent dual active odorants induce distinct signal transduction pathways at different subcellular localizations, which affect both neuronal signaling, resulting in odor perception, and the ER-dependent transcriptional control of specific genes. We demonstrate these effects using fluorescence-based in vitro and cellular assays. Among these odorants, we have identified synthetic sandalwood compounds, an important class of molecules used in the fragrance industry. For one estrogenic odorant we have also identified the cognate OR. This prompted us to compare basic molecular recognition principles of odorants on the two structurally and apparent functionally non-related receptors using computational modeling in combination with functional assays. Faced with the increasing evidence that ORs may perform chemosensory functions in a number of tissues outside of the nasal olfactory epithelium, the unraveling of these molecular ligand-receptor interaction principles is of critical importance. In addition the evidence that certain olfactory sensory neurons naturally co-express ORs and ERs may provide a direct functional link between the olfactory and hormonal systems in humans. Our results are therefore useful for defining the structural and functional characteristics of ER-specific odorants and the role of odorant molecules in cellular processes other than olfaction.Our nose detects a large variety of odorant signals relying on about 350 different predicted G-protein-coupled olfactory receptors (ORs) 3 with a conserved seven-transmembrane helical structure (1-3). By binding odorant molecules ORs modulate the conversion of chemical into electrical neuronal signals that are finally decoded in higher brain regions to trigger emotional and behavioral responses (4 -6). Odorants are generally small, hydrophobic organic molecules with highly variable chemical structures and properties (7). They easily pass cell membranes, and, due to their enormous chemical diversity, some of them might, apart from their "conventional" role in olfaction, trigger also yet unknown cellular processes. The role of specific ORs in sperm chemotaxis has been documented (8,9), and the widespread ectopic expression of OR genes in a large number of non-olfactory human tissues implicates additional, unproven functions of ORs in embryonic development and cell-cell recognition (10), and proliferation rates in prostate cancer cells (11). Recent findings indicate that ORs might also have chemosensory functions in kidney (12). Although most present efforts concentrate on matching odorants with their cognate ORs to define their molecular receptive ranges and receptor fu...

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Section: Resultsmentioning

confidence: 91%

Dual Activities of Odorants on Olfactory and Nuclear Hormone Receptors

Pick

Etter

Baud

et al. 2009

Journal of Biological Chemistry

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“…However, a second effect of fulvestrant is the aggregation of the newly synthesized ER in the cytoplasm (3–5). Such aggregation is not observed following treatment with tamoxifen and occurs following the disappearance of the ER in the nucleus (5).…”

Section: Introductionmentioning

confidence: 99%

“…Such aggregation is not observed following treatment with tamoxifen and occurs following the disappearance of the ER in the nucleus (5). Despite these findings, the current view of the mode of action of fulvestrant only considers its effect on the degradation of the ER in the nucleus.…”

Section: Introductionmentioning

confidence: 99%

Bortezomib Enhances the Efficacy of Fulvestrant by Amplifying the Aggregation of the Estrogen Receptor, Which Leads to a Proapoptotic Unfolded Protein Response

Ishii

Papa

Bahadur

et al. 2011

Clinical Cancer Research

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Purpose Fulvestrant is known to promote the degradation of the estrogen receptor (ER) in the nucleus. However, fulvestrant also promotes the aggregation of the newly synthesized ER in the cytoplasm. Accumulation of protein aggregates leads to cell death but this effect is limited as a result of their elimination by the proteasome. We tested whether combining fulvestrant with the proteasome inhibitor, bortezomib, could enhance the accumulation of ER aggregates and cause apoptotic cell death. Experimental Design The rate of aggregation of the ER was monitored in ER+ breast cancer cells lines, T47D, ZR-75.1, BT474, MDA-MB-361, MCF-7, fulvestrant resistance MCF-7, and tamoxifen-resistant T47D-cyclin D1 cells. Activation of the unfolded protein response, apoptosis, and metabolic rate were also monitored in these cell lines following treatment with fulvestrant, bortezomib, or bortezomib in combination with fulvestrant. Results We found that bortezomib enhances the fulvestrant-mediated aggregation of the ER in the cytoplasm without blocking the degradation of the ER in the nucleus. Further, these aggregates activate a sustained unfolded protein response leading to apoptotic cell death. Further, we show that the combination induced tumor regression in a breast cancer mouse model of tamoxifen resistance. Conclusions Adding bortezomib to fulvestrant enhances its efficacy by taking advantage of the unique ability of fulvestrant to promote cytoplasmic aggregates of the ER. As this effect of fulvestrant is independent of the transcriptional activity of the ER, these results suggest that this novel combination may be effective in breast cancers that are ER+ but estrogen independent.

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“…This novel approach paves the way for imaging the biophysical environment of specific GFP-tagged proteins in live cells. A pulse labeling of AGT-ER(the human estrogen receptor alpha with human O6-alkylguanine-DNA alkyltransferase) fusion proteins with different fluorophores was presented as a novel tool for investigating the functional regulation of nuclear receptors in individual cells [40].…”

Section: Receptors and Ligands On Membranementioning

confidence: 99%

Application of Probes in Live Cell Imaging~!2010-01-03~!2010-05-09~!2010-08-16~!

Chen¹,

Bai²,

Wang³

2010

JEBP

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Live cell imaging (LCI) is the approach of non-invasively analyzing dynamic processes in living cells using state-of-the-art microscopy and computer vision techniques. LCI provides exciting and novel insights into cell biology. The present review summarized LCI research in recent years and detailed the role of probes in LCI. We discussed the basic principle and development in LCI technology, including fluorecence resonance energy transfer, fluorescence lifetime imaging microscopy, atomic force microscopy, scanning ion conductance microscopy, confocal microscopy, two-photon excitation fluorescence microscopy and Cell-IQ® System . Then we listed several probes such as green fluorescent protein and quantum dots which are the most widely used probes. Proteins, organelles, nucleotides and other chemicals related to cell biology may all be potential targets. We also discussed the advantages and disadvantages of different probes. Although specific probes in LCI still need to be explored, the application of LCI may be attractive for better understanding of cellular functions.

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Distribution Plasticity of the Human Estrogen Receptor α in Live Cells: Distinct Imaging of Consecutively Expressed Receptors

Cited by 11 publications

References 56 publications

Dual Activities of Odorants on Olfactory and Nuclear Hormone Receptors

Dual Activities of Odorants on Olfactory and Nuclear Hormone Receptors

Bortezomib Enhances the Efficacy of Fulvestrant by Amplifying the Aggregation of the Estrogen Receptor, Which Leads to a Proapoptotic Unfolded Protein Response

Application of Probes in Live Cell Imaging~!2010-01-03~!2010-05-09~!2010-08-16~!

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